Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Terri T. Ni; Eric J. Rellinger; Amrita Mukherjee; Shuying Xie; Lauren Stephens; Curtis A. Thorne; Kwangho Kim; Jiangyong Hu; Ethan Lee; Larry Marnett; Antonis K. Hatzopoulos; Tao P. Zhong

doi:10.1016/j.chembiol.2011.09.015

Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Terri T. Ni, Eric J. Rellinger, Amrita Mukherjee, Shuying Xie, Lauren Stephens, Curtis A. Thorne, Kwangho Kim, Jiangyong Hu, Ethan Lee, Larry Marnett, Antonis K. Hatzopoulos, Tao P. Zhong

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

We have developed a robust in vivo small-molecule screen that modulates heart size and cardiomyocyte generation in zebrafish. Three structurally related compounds (Cardionogen-1 to Cardionogen-3) identified from our screen enlarge the size of the developing heart via myocardial hyperplasia. Increased cardiomyocyte number in Cardionogen-treated embryos is due to expansion of cardiac progenitor cells. In zebrafish embryos and murine embryonic stem (ES) cells, Cardionogen treatment promotes cardiogenesis during and after gastrulation, whereas it inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/β-catenin signaling activity. We demonstrate that Cardionogen inhibits Wnt/β-catenin-dependent transcription in murine ES cells and zebrafish embryos. Cardionogen can rescue Wnt8-induced cardiomyocyte deficiency and heart-specific phenotypes during development. These findings demonstrate that in vivo small-molecule screens targeting heart size can reveal compounds with cardiomyogenic effects and identify underlying target pathways.

Original language	English
Pages (from-to)	1658-1668
Number of pages	11
Journal	Chemistry and Biology
Volume	18
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2011.09.015
State	Published - Dec 23 2011

Bibliographical note

Funding Information:
We are indebted to John Guan for his invaluable assistance in fish care and Alex Waterson for his efforts in chemical synthesis. We thank Geoffrey Burns for cmlc2-EGFP and cmlc2-DsRed fish, Randall Moon for hsp-wnt8 fish, G.J. Robbins for providing Myh6 promoter plasmid, and P. ten Dijke for BRE 2 -Luc construct. We are grateful to Bruce Appel, Scott Baldwin, Wenbiao Chen, Josh Gamse, Daqing Jin, and members of our laboratories for comments on the manuscript and helpful discussions. This research is supported in part by grants NIH-NS064852 (T.P.Z.), HL083958 (A.K.H.), NIH-UL1RR024975 (VICTR), and Fudan University-EZH1322001 (T.P.Z.).

Funding

We are indebted to John Guan for his invaluable assistance in fish care and Alex Waterson for his efforts in chemical synthesis. We thank Geoffrey Burns for cmlc2-EGFP and cmlc2-DsRed fish, Randall Moon for hsp-wnt8 fish, G.J. Robbins for providing Myh6 promoter plasmid, and P. ten Dijke for BRE 2 -Luc construct. We are grateful to Bruce Appel, Scott Baldwin, Wenbiao Chen, Josh Gamse, Daqing Jin, and members of our laboratories for comments on the manuscript and helpful discussions. This research is supported in part by grants NIH-NS064852 (T.P.Z.), HL083958 (A.K.H.), NIH-UL1RR024975 (VICTR), and Fudan University-EZH1322001 (T.P.Z.).

Funders	Funder number
Fudan University-EZH1322001
NIH-NS064852	HL083958, NIH-UL1RR024975
National Institute of Neurological Disorders and Stroke	R21NS064852

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2011.09.015

Cite this

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title = "Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling",

abstract = "We have developed a robust in vivo small-molecule screen that modulates heart size and cardiomyocyte generation in zebrafish. Three structurally related compounds (Cardionogen-1 to Cardionogen-3) identified from our screen enlarge the size of the developing heart via myocardial hyperplasia. Increased cardiomyocyte number in Cardionogen-treated embryos is due to expansion of cardiac progenitor cells. In zebrafish embryos and murine embryonic stem (ES) cells, Cardionogen treatment promotes cardiogenesis during and after gastrulation, whereas it inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/β-catenin signaling activity. We demonstrate that Cardionogen inhibits Wnt/β-catenin-dependent transcription in murine ES cells and zebrafish embryos. Cardionogen can rescue Wnt8-induced cardiomyocyte deficiency and heart-specific phenotypes during development. These findings demonstrate that in vivo small-molecule screens targeting heart size can reveal compounds with cardiomyogenic effects and identify underlying target pathways.",

author = "Ni, {Terri T.} and Rellinger, {Eric J.} and Amrita Mukherjee and Shuying Xie and Lauren Stephens and Thorne, {Curtis A.} and Kwangho Kim and Jiangyong Hu and Ethan Lee and Larry Marnett and Hatzopoulos, {Antonis K.} and Zhong, {Tao P.}",

note = "Funding Information: We are indebted to John Guan for his invaluable assistance in fish care and Alex Waterson for his efforts in chemical synthesis. We thank Geoffrey Burns for cmlc2-EGFP and cmlc2-DsRed fish, Randall Moon for hsp-wnt8 fish, G.J. Robbins for providing Myh6 promoter plasmid, and P. ten Dijke for BRE 2 -Luc construct. We are grateful to Bruce Appel, Scott Baldwin, Wenbiao Chen, Josh Gamse, Daqing Jin, and members of our laboratories for comments on the manuscript and helpful discussions. This research is supported in part by grants NIH-NS064852 (T.P.Z.), HL083958 (A.K.H.), NIH-UL1RR024975 (VICTR), and Fudan University-EZH1322001 (T.P.Z.). ",

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AU - Thorne, Curtis A.

AU - Kim, Kwangho

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AU - Lee, Ethan

AU - Marnett, Larry

AU - Hatzopoulos, Antonis K.

AU - Zhong, Tao P.

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Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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